A phase I study of the safety, tolerability, and pharmacokinetics of contezolid acefosamil after intravenous and oral administration in healthy Chinese subjects

ABSTRACT Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects (n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500–2,000 mg), the corresponding C max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC0–inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T max from 2.00 to 2.75 h, and mean t 1/2 from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20–2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid C max of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC0–inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max and AUC0–inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.

FIG S1 Goodness-of-fit plots for the final population pharmacokinetic model of intravenous contezolid acefosamil.(A) Observed concentration (DV) versus population predicted concentration (PRED).(B) DV versus individual predicted concentration (IPRED).(C) Conditional weighted residuals (CWRES) versus time.(D) CWRES versus PRED.The solid lines in (A) and (B) represent the line of identity, whereas the solid lines in (C) and (D) denote the position where CWRES is equal to 0. The blue lines are regression lines and the red lines represent the distribution of data in (C) and (D).
These steady-state data were the mean values of 9 subjects because the data of one subject were invalid due to nausea and vomiting on Day 9 and Day 11.AUC, area under the concentration-time curve; AUC 0-inf , the area under the concentration-time curve from time 0 to infinity; AUC tau,ss , the steady-state AUC over a dosing interval; C max , peak concentration; C max, ss , steady-state peak concentration; C min, ss , steady-state trough concentration; MRT, mean retention time; NA, not applicable; PK, pharmacokinetic; t 1/2 , elimination half-life; t 1/2,ss , elimination half-life at steady state; T max , time to peak concentration; T max, ss , time to peak concentration at steady state; λ z , apparent terminal elimination rate constant.
bData are presented as median (minimum, maximum) for T max or mean (SD) unless otherwise specified.a Subject 2A206 was excluded from this PK analysis due to nausea and vomiting.b

TABLE S2
Power model analysis to characterize the effect of dosage on the main pharmacokinetic parameters of MRX-1352, contezolid, MRX-1320 (M2) after intravenous administration of single ascending dose (500-2000 mg) of contezolid acefosamil Slope was obtained from the power model: Ln(PK) = Intercept + slope × Ln(X/Xmedian), where PK indicates pharmacokinetic parameters, X means independent variable (dosage), and Xmedian is the median of independent variable.CI, confidence interval.

TABLE S3
Final model parameter estimates and bootstrap results

Table S4
The simulated AUC0-24h of contezolid in terms of body weight on Day 1 and Day 14 after IV infusion of 2000 mg contezolid acefosamil over 1 h followed by a maintenance dose of 1000 mg, administered twice daily for 14 consecutive days based on the population PK model.

TABLE S5
Timetable for blood sample collection